This work seeks to clarify the nature of the cells of origin of acute lymphoblastic leukemia and to elucidate the factors which regulate the growth and differentiation of such cells. The results of our studies to date indicate that this type of leukemia is heterogeneous and arises from one of at least 4 different cell types: sheep erythrocyte rosette-forming T cells, surface immunoglobulin bearing B cells, human T lymphocyte antigen-positive (HTLA ion) null cells, and human B lymphocyte antigen-positive (HBLA ion) null cells. Investigations into the nature of cells contained within the HTLA ion and HBLA ion null cell subsets of normal subjects have shown that thymosin-responsive T cell precursors and natural killer cells belong to the HTLA ion null cell subset, whereas immature myeloid precursors belong to the HBLA ion null cell subset.